The cells which make bone, osteoblasts, and those which resorb bone, osteoclasts, have very precise functions. The balance between their activities is critical to the maintenance of the skeletal system.
Osteoclasts are large, multinucleated cells. They have high capacities for the synthesis and storage of enzymes, including acid hydrolases and carbonic anhydrase isoenzyme II. Osteoclasts are derived from mononuclear cells that are the progeny of stem-cell populations located in the bone marrow, spleen, and liver. Proliferation of these stem-cell populations produces the mononuclear precursors of osteoclasts, which migrate via vascular routes to skeletal sites. These cells then differentiation and fuse with each other to form osteoclasts, or fuse with existing osteoclasts.
Activation of osteoclasts to resorb bone is generally thought to involve release of organic acids and membrane-bound packages of enzymes onto the bone surface. This requires elaboration next to the bone surface of a specialized region of the plasma membrane, the ruffled border. In this region the osteoclast's prepackaged, membrane-bound enzymes can fuse with the plasma membrane and be released onto the bone surface in a confined extracellular space. Degradation of the inorganic and organic tissue occurs in this area. The products of resorption are then taken up via endocytosis for additional intracellular processing within cytoplasmic vacuoles.
Osteopetrosis is an inherited defect characterized by a failure of normal bone resorption (modeling) and, as a result, excessive bone accumulation throughout the skeleton. Osteopetrosis occurs in a number of species, including man. The disease represents a heterogeneous group of bone disorders both in animal species demonstrating these defects and in the infantile malignant forms of osteopetrosis. The skeletal sclerosis and reduced bone marrow resorption in certain animal species have been shown to be due to defective osteoclasts. The skeletal abnormalities associated with osteopetrosis lead to a number of problems, including anemia, infection, optic atrophy, deafness and various neuropathies. The life expectancy of osteopetrotic patients is less than ten years.
Presently available forms of treatment for osteopetrotic children include bone marrow transplantation and interferon-gamma therapy. Bone marrow transplantation is not available to most osteopetrotic children and not all children who receive bone marrow transplants respond favorably. Interferon-gamma therapy has demonstrated moderate success in stimulating osteoclast function (Key et al., J. Pediatr. 121, 119-24, 1992) but requires high doses and extensive clinical monitoring to avoid the potential toxic effects associated with this cytokine.
The study of osteopetrosis has been facilitated by the existence of a number of osteopetrotic animal mutations. For a discussion of such mutations, see Marks, Clinical Orthopedics, 180, 239-263, 1984. The "incisors-absent" (ia) (Greep, J. Hered. 32:397, 1941) and osteopetrotic (op) (Moutier et l., Animal 6:87, 1973) rat mutations, as well as certain other animal congenital osteopetrotic mutations, have been shown to respond to spleen cell or bone marrow transplantation (Marks, Am. J. Anat. 146:331, 1976; Milhaud et al., C.R. Acad. Sci. Paris 280:2485, 1975), thereby paving the way for the first successful reported treatment of congenital human osteopetrosis by Ballet et al., Lancet 2:1137, 1977. Hence these mutations provide an acceptable corollary to human osteopetrosis.
Inflammation-mediated bone loss occurs in numerous diseases such as osteoporosis, periodontal disease, osteoarthritis, and rheumatoid arthritis. Osteoporosis is a major skeletal disease characterized by low bone mass, architectural deterioration, and an increased risk of fracture. It is implicated in more than 1.5 million fractures per year in the United States. There is evidence of significant mortality and morbidity associated with osteoporosis. The cost of osteoporotic fractures in the United States is estimated at $7-10 billion annually.
As peak bone mass is attained, usually between the ages of 35 and 40 in humans, a slight imbalance occurs between the processes of bone formation by osteoblasts and bone resorption by osteoclasts. The amount of bone resorbed by osteoclasts is not entirely replaced by osteoblasts. The speed of bone remodeling (bone turnover) increases after menopause. The outcome is accelerated loss of bone and a negative calcium balance.
Bone loss in the oral cavity is likewise a significant problem in the United States. Interdisciplinary attention has recently focused on possible relationship between osteoporosis and oral bone loss (Proceedings of the Workshop on Oral Bone Loss and Osteoporosis, Leesburg, Va., Aug. 26-28, 1992, in J. Bone Miner. Res. 8, Supplement 2, 1993).
Periodontitis is characterized by loss of bone and soft tissue attachment. The response to the formation of microbial plaque is an inflammation of the gingiva and the resulting breakdown of tissues. This causes the formation of an opening along the tooth surface known as the "periodontal pocket". The bone remodeling that occurs in periodontal disease is typically localized to the alveolar bone. The mechanism of alveolar bone loss in periodontal disease is believed to be the same basic mechanism as is responsible for bone loss associated with other types of inflammatory conditions. It has been presumed that accumulations of chronic inflammatory cells generate inflammatory cytokines and local mediators that are responsible for enhanced osteoclastic resorption and inhibition of repair or new bone formation at the sites of resorption. For instance, inflammatory mediators, such as prostaglandins (Offenbacher et al., J. Periodont. Res. 21, 101-112, 1986) have been associated with active progression of periodontitis. IL-1, another mediator of inflammation, has been found in gingival crevicular fluid during inflammation (Charon et al., Infect. Immun. 38, 1190-95, 1982).
Inflammation-mediated bone loss is a problem of major clinical and economic significance. Studies attempting to identify the factor(s) which mediate bone loss have implicated various immune cell products, i.e. cytokines and growth factors. For a recent short review see Mundy, J. Bone Miner. Res. 8, Supplement 2, S505-S510, 1993. It has been suggested that the major mediators likely involved include interleukin 1, tumor necrosis factor-.alpha., lymphotoxin, interleukin 6, prostaglandins of the E series, leukotrienes, lipopolysaccharide, transforming growth factor-.beta., and the colony-stimulating factors. But no studies have provided conclusive evidence of cytokines' pathogenic role in bone degradation. Some studies have yielded conflicting data. The production of a particular cytokine may be elevated in some patients but not in others, yet all have the same disease and demonstrate similar amounts of bone loss. Based on these studies, the treatment strategies designed to help prevent the bone loss associated with inflammation have either been ineffective or have shown limited therapeutic efficacy in a subset of patients with a specific disease.